Showing papers on "Myoepithelial cell published in 2004"

Expression Profiling of Purified Normal Human Luminal and Myoepithelial Breast Cells: Identification of Novel Prognostic Markers for Breast Cancer

Abstract: The normal duct-lobular system of the breast is lined by two epithelial cell types, inner luminal secretory cells and outer contractile myoepithelial cells. We have generated comprehensive expression profiles of the two normal cell types, using immunomagnetic cell separation and gene expression microarray analysis. The cell-type specificity was confirmed at the protein level by immunohistochemistry in normal breast tissue. New prognostic markers for survival were identified when the luminal- and myoepithelial-specific molecules were evaluated on breast tumor tissue microarrays. Nuclear expression of luminal epithelial marker galectin 3 correlated with a shorter overall survival in these patients, and the expression of SPARC (osteonectin), a myoepithelial marker, was an independent marker of poor prognosis in breast cancers as a whole. These data provide a framework for the interpretation of breast cancer molecular profiling experiments, the identification of potential new diagnostic markers, and development of novel indicators of prognosis.

Dysregulated Expression of Adamalysin-Thrombospondin Genes in Human Breast Carcinoma

Abstract: The adamalysin-thrombospondin (ADAMTS) proteinases are a relatively newly described branch of the metzincin family that contain metalloproteinase, disintegrin, and thrombospondin motifs. They have been implicated in various cellular events, including cleavage of proteoglycans, extracellular matrix degradation, inhibition of angiogenesis, gonadal development, and organogenesis. However, in many cases, their normal physiological roles and their potential for dysregulation in malignancy remain to be established. The expression profile of ADAMTS1-20 in human breast carcinoma was undertaken by real-time PCR using RNA isolated from malignant tumors, nonneoplastic mammary tissue, and breast cancer cell lines to identify altered regulation that may have potential pathogenetic and prognostic significance. Our studies show that seven of the ADAMTS genes (ADAMTS1, 3, 5, 8, 9, 10, and 18) are consistently down-regulated in breast carcinomas with respect to nonneoplastic mammary tissue, irrespective of the heterogeneity of the samples and the tumor type or grade (Mann-Whitney U test, P < 0.0001 for each gene). Conversely, ADAMTS4, 6, 14, and 20 are consistently up-regulated in breast carcinomas (P = 0.005, P < 0.0001, P = 0.003, and P = 0.001, respectively). ADAMTS2, 7, 12, 13, 15, 16, 17, and 19 show no significant difference between the sample types. ADAMTS1, 2, 7, 8, 10, and 12 are expressed predominantly in stromal fibroblasts. ADAMTS3, 4, 5, 6, 9, and 13-20 inclusive are expressed predominantly in myoepithelial cells; all appear to be relatively poorly expressed in luminal epithelial cells. ADAMTS15 has emerged as being an independent predictor of survival, with RNA expression levels significantly lower (P = 0.007) in grade 3 breast carcinoma compared with grade 1 and 2 breast carcinoma.

p63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma.

Abstract: p63, a member of the p53 gene family, is involved in cellular differentiation and is expressed in the nuclei of myoepithelial cells of normal breast ducts and lobules. Although p63 has been reported in metaplastic carcinomas of the breast, its expression pattern in breast carcinomas and sarcomas has not been fully characterized, and its potential diagnostic utility has not been defined. In this study, we determined p63 expression in a large number of breast carcinomas, including metaplastic carcinomas, and in Phyllodes tumors and sarcomas. We examined 189 invasive breast carcinomas, including 15 metaplastic carcinomas, as well as 10 Phyllodes tumors, and 5 pure sarcomas of the breast for pattern and intensity of p63 staining using an anti-p63 antibody (clone 4A4, Neomarkers). p63 was strongly expressed in 13 of 15 metaplastic carcinomas (86.7%). p63 was positive in all the metaplastic carcinomas with spindle cell and/or squamous differentiation (12 of 12), and in 1 of 3 metaplastic carcinomas with cartilage foci. In stark contrast, only 1 of 174 (0.6%) nonmetaplastic invasive carcinomas was positive for p63. All Phyllodes tumors and sarcomas were consistently negative for p63 expression. The sensitivity and specificity of p63 as a diagnostic marker for metaplastic carcinoma was 86.7% and 99.4%, respectively. We propose the inclusion of p63 as part of the diagnostic workup of challenging spindle cell tumors of the breast as a highly specific marker for metaplastic carcinomas.

Current practical applications of diagnostic immunohistochemistry in breast pathology.

Abstract: In recent years, immunohistochemistry has assumed an increasingly prominent role in diagnostic breast pathology. Immunohistochemistry is now frequently used in the evaluation of many epithelial proliferations of the breast. Common applications include the use of myoepithelial markers to evaluate for stromal invasion, E-cadherin to distinguish between ductal and lobular neoplasia, high molecular weight cytokeratins to differentiate usual ductal hyperplasia from ductal carcinoma in situ, immunohistochemical profiles to characterize site of origin of metastatic carcinomas, and cytokeratin stains to detect metastases in sentinel lymph nodes. Recent advances, practical considerations, and potential pitfalls in the use of immunohistochemistry in these five diagnostic categories are discussed herein.

Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma

Abstract: In the setting of inactivated DNA damage-sensitive checkpoints, critically shortened telomeres promote chromosomal instability and the types of widespread cytogenetic alterations that characterize most human carcinomas. Using a direct telomere fluorescence in situ hybridization technique, we analyzed 114 invasive breast carcinomas, 29 carcinoma in situ lesions, 10 benign proliferative lesions, and different normal epithelial components of the male and female breast. We found marked telomere shortening in the majority (52.5%) of invasive carcinomas; smaller subsets of invasive carcinoma demonstrated moderate telomere shortening (17.5%) or normal telomere lengths (21%), while a small subgroup (5%) contained elongated telomeres. Strikingly, the majority (78%) of ductal carcinoma in situ demonstrated markedly or moderately shortened telomeres. Surprisingly, unlike all other normal epithelia studied to date, moderate telomere shortening was observed in benign secretory cells in approximately 50% of histologically-normal terminal duct lobular units (from which most breast cancer is thought to arise), while such shortening was not seen in myoepithelial cells or normal large lactiferous ducts of the female breast or male breast ducts (from which breast cancer infrequently arises). We postulate that such shortening is the result of hormonally driven, physiological proliferation, and may delineate a population of epithelial cells at risk for subsequent malignant transformation.

Low-grade salivary duct carcinoma: description of 16 cases.

Abstract: Low-grade salivary duct carcinoma is a rare neoplasm. We report on 16 patients, with a median age of 64 years. All but one tumor arose from the parotid gland, including one tumor that arose in an intraparotid lymph node; one arose in the submandibular gland. Tumors consist of single to multiple dominant cysts, accompanied by adjacent intraductal proliferation. Cysts are lined by small, multilayered, proliferating, bland ductal cells with finely dispersed chromatin and small nucleoli. Separate, smaller ductal structures are variably filled by proliferating ductal epithelium with cribriform, micropapillary, and solid areas. The overall appearance is very similar to breast atypical ductal hyperplasia and low-grade ductal carcinoma in situ. Foci of definitive stromal invasion were seen in four tumors. Two tumors demonstrated transition from low- to intermediate- or high-grade cytology, with scattered mitotic figures and focal necrosis. S-100 revealed diffuse strong expression in all 9 cases studied. Myoepithelial markers (calponin) highlighted supportive myoepithelial cells rimming the cystic spaces, confirming the intraductal nature of most, or all, of six tumors studied. Nine tumors studied for Her2-neu antigen were uniformly negative. Follow-up was obtained on 13 of our 16 patients. All patients were disease-free after surgery 6 to 132 months (median 30 months). Low-grade salivary duct carcinoma is a low-grade neoplasm with an excellent prognosis; it may be treated by conservative but complete resection. Its resemblance to atypical breast ductal hyperplasia, or micropapillary/cribriform intraductal carcinoma, distinguishes it from high-grade salivary duct carcinoma, papillocystic acinic cell carcinoma, and cystadenocarcinoma.

Expression of histone deacetylase 8, a class I histone deacetylase, is restricted to cells showing smooth muscle differentiation in normal human tissues.

Abstract: Histone deacetylases (HDACs) were originally identified as nuclear enzymes involved in gene transcription regulation. Until recently, it was thought that their activity was restricted within the nucleus, with histones as unique substrates. The demonstration that specific HDACs deacetylate nonhistone proteins, such as p53 and α-tubulin, broadened the field of activity of these enzymes. HDAC8, a class I HDAC, is considered to be ubiquitously expressed, as suggested by results of Northern blots performed on tissue RNA extracts, and transfection experiments using various cell lines have indicated that this enzyme may display a prominent nuclear localization. Using immunohistochemistry, we unexpectedly found that, in normal human tissues, HDAC8 is exclusively expressed by cells showing smooth muscle differentiation, including visceral and vascular smooth muscle cells, myoepithelial cells, and myofibroblasts, and is mainly detected in their cytosol. These findings were confirmed in vitro by nucleo-cytoplasmic fractionation and immunoblot experiments performed on human primary smooth muscle cells, and by the cytosolic detection of epitope-tagged HDAC8 overexpressed in fibroblasts. Immunocytochemistry strongly suggested a cytoskeleton-like distribution of the enzyme. Further double-immunofluorescence staining experiments coupled with confocal microscopy analysis showed that epitope-tagged HDAC8 overexpressed in murine fibroblasts formed cytoplasmic stress fiber-like structures that co-localized with the smooth muscle cytoskeleton protein smooth muscle α-actin. Our works represent the first demonstration of the restricted expression of a class I HDAC to a specific cell type and indicate that HDAC8, besides being a novel marker of smooth muscle differentiation, may play a role in the biology of these contractile cells.

Assessment of p63 expression in the salivary gland neoplasms adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and basal cell and canalicular adenomas

Abstract: Purpose The purpose of this study was to determine the extent of p63 immunoreactivity in the malignant salivary gland neoplasms adenoid cystic carcinoma (ACC) and polymorphous low-grade adenocarcinoma (PLGA) and to compare this to the expression of this marker in the benign salivary gland tumors canalicular adenoma and basal cell adenoma. Few studies on the expression of p63 in head and neck salivary gland tumors have been published to date. P63, a selective immunohistochemical marker of basal/stem cells of stratified epithelium and of myoepithelial cells, is a p53 homologue that plays an essential role in both morphogenesis of epidermis and limb development. P63 immunoreactivity has been demonstrated in squamous cell and urothelial carcinomas. It is generally absent in most nonsquamous cell carcinomas. Study design Formalin-fixed paraffin-embedded sections from 49 salivary gland neoplasms, representing 6 canalicular adenomas, 11 basal cell adenomas, 17 PLGA and 15 ACC accessioned from 1989 to 2002 by the Department of Pathology, Long Island Jewish Medical Center, New Hyde Park, NY, were stained with an anti-p63 monoclonal antibody. Results Nuclear p63 reactivity was uniformly positive in PLGA (17/17, 100%). Positive reactivity was also identified in the majority of cases of ACC (13/15, 87%), primarily in the nonluminal myoepithelial-like cells surrounding luminal cells. Canalicular adenoma did not exhibit any p63 immunoreactivity. All basal cell adenomas of parotid origin stained strongly for p63, with staining localized to the peripheral tumor cells situated adjacent to the connective tissue stroma. None of the basal cell adenomas originating in the upper lip stained with p63. In native adjacent salivary gland tissue, p63 reactivity was identified focally in the nuclei of myoepithelial and basal duct cells. Conclusions P63 is strongly expressed in basal cell adenoma of parotid origin, and in ACC and PLGA. Canalicular adenoma did not demonstrate p63 staining, consistent with this tumor's putative luminal ductal cell differentiation. Our results suggest that the neoplastic cells in PLGA may represent either a population of p63-positive epithelial stem/reserve cells similar to the basal cells of stratified epithelium, or modified myoepithelial cells. Given the staining pattern of the tumors examined, p63 does not appear to be an ideal marker for distinguishing between ACC, PLGA, and basal cell adenoma.

Endometase/matrilysin-2 in human breast ductal carcinoma in situ and its inhibition by tissue inhibitors of metalloproteinases-2 and -4: a putative role in the initiation of breast cancer invasion.

Abstract: Local disruption of the integrity of both the myoepithelial cell layer and the basement membrane is an indispensable prerequisite for the initiation of invasion and the conversion of human breast ductal carcinoma in situ (DCIS) to infiltrating ductal carcinoma (IDC). We previously reported that human endometase/matrilysin-2/matrix metalloproteinase (MMP) 26-mediated pro-gelatinase B (MMP-9) activation promoted invasion of human prostate carcinoma cells by dissolving basement membrane proteins (Y. G. Zhao et al. , J. Biol. Chem., 278: 15056–15064, 2003). Here we report that tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4 are potent inhibitors of MMP-26, with apparent K i values of 1.6 and 0.62 nm, respectively. TIMP-2 and TIMP-4 also inhibited the activation of pro-MMP-9 by MMP-26 in vitro . The expression levels of MMP-26, MMP-9, TIMP-2, and TIMP-4 proteins in DCIS were significantly higher than those in IDC, atypical intraductal hyperplasia, and normal breast epithelia adjacent to DCIS and IDC by immunohistochemistry and integrated morphometry analysis. Double immunofluorescence labeling and confocal laser scanning microscopy revealed that MMP-26 was colocalized with MMP-9, TIMP-2, and TIMP-4 in DCIS cells. Higher levels of MMP-26 mRNA were also detected in DCIS cells by in situ hybridization.

Ceruminous adenomas: a clinicopathologic study of 41 cases with a review of the literature.

Abstract: Background: Ceruminous gland neoplasms are rare neoplasms. To date, a large clinicopathologic study of benign ceruminous gland neoplasms has not been reported. Design: Forty-one cases of ceruminous gland adenomas diagnosed between 1970 and 2000 were retrieved from the files of the Armed Forces Institute of Pathology. Histologic features were reviewed, immunohistochemical analysis was performed (n = 21), and patient follow-up was obtained (n = 40). Results: The patients included 22 men and 19 women, 24 to 85 years of age (mean, 54.2 years). Patients presented clinically with a painless mass of the outer half of the external auditory canal (n = 33) or with hearing changes (n = 11). Symptoms were present for an average of 16.3 months. The polypoid masses affected the external auditory canal only and ranged in size from 0.4 to 2 cm in greatest dimension (mean, 1.1 cm). Histologically, the tumors demonstrated glands and small cysts lined by a tubuloglandular proliferation of inner ceruminous cells (cerumen-secreting epithelium with decapitation secretion) subtended by a spindled to cuboidal myoepithelial layer. A hyalinized stroma created an infiltrative pattern of growth; surface involvement (n = 8) was seen. Tumors were divided into ceruminous adenoma (n = 36), ceruminous pleomorphic adenoma (n = 4), and syringocystadenoma papilliferum (n = 1) types. The luminal cells were strongly and diffusely immunoreactive with CK7, while the basal cells were highlighted with CK5/6, S-100 protein, and p63. CDI 17 highlighted the luminal cells preferentially. The proliferation markers revealed a low index. Adenocarcinoma and middle ear adenoma are the principal differential consideration. Surgical excision was used in all patients. Four patients developed a recurrence due to incomplete excision. All patients were without evidence of disease at the last follow-up: alive (n = 28, mean 16.3 years) or dead (n = 12, mean 11.8 years). Conclusion: Ceruminous gland adenomas are the most common external auditory canal tumors. They demonstrate a dual cell population of basal myoepithelial-type cells and luminal ceruminous (ceruminal) cells. Cerumen pigment, CK7, and p63 can help to distinguish this tumor from other neoplasms that occur in the region. Complete surgical excision results in an excellent long-term clinical outcome.

p53 overexpression and mutation in metaplastic carcinoma of the breast: genetic evidence for a monoclonal origin of both the carcinomatous and the heterogeneous sarcomatous components.

Abstract: Metaplastic carcinoma of the breast (MCB) is characterized by the biphasic presence of both a carcinomatous component (CC) and heterogeneous sarcomatous components (HSCs). Although an epithelial or myoepithelial origin of the HSCs has been suggested, molecular evidence for a common origin for the CC and HSCs is limited and the mechanism underlying the sarcomatous or metaplastic change is unknown. The present study investigated the frequency and nature of p53 expression and mutation in 11 biphasic and three monophasic MCBs by immunohistochemistry and either needle-assisted or laser-capture microdissection, followed by PCR and direct sequencing. In all 11 biphasic MBCs, staining for p53 was concordant in the CC and HSCs (8/11 positive and 3/11 negative), consistent with a monoclonal origin of both components. Significantly, whenever a component of carcinoma in situ was present (5/11), the p53 staining was always concordant with that in the CC and HSCs. Screening of the 14 cases for p53 mutation identified four mutants, each in a single case of biphasic MCB with concordant p53 overexpression. Both the CC and each of the HSCs revealed identical p53 mutation in all four cases; in addition, one of the four cases also had an in situ component and the same mutant was found simultaneously in the in situ, invasive, and sarcomatous components. The concordant pattern of p53 alteration (overexpression or mutation) implies that early p53 mutation, occurring prior to invasion, was maintained throughout tumour progression and metaplastic change. The findings therefore support a monoclonal histogenesis of the various components, but are neutral regarding the role of p53 alteration in the development of metaplastic change in MCBs.

Distribution and significance of 14-3-3σ, a novel myoepithelial marker, in normal, benign, and malignant breast tissue

Abstract: 14-3-3sigma is a candidate tumour suppressor gene transactivated by p53 in response to DNA damage. In gene expression analysis of normal luminal and myoepithelial cells, 14-3-3sigma was preferentially expressed by myoepithelial cells. This study has analysed the immunohistochemical distribution and subcellular localization of 14-3-3sigma in normal breast tissue and in a large series of benign and malignant breast lesions on whole tissue sections and by tissue microarray. Immunohistochemistry demonstrated that 14-3-3sigma was consistently expressed in the cytoplasmic compartment and occasionally in the nuclei of myoepithelial cells arranged as a continuous layer around normal ducts and lobular units, whereas luminal epithelial, stromal, endothelial, pericytic, lipomatous, and neural cells showed no staining. Myoepithelial cells of benign proliferations and pre-invasive lesions were consistently positive for 14-3-3sigma. Strong expression of 14-3-3sigma was evident in one case of ductal carcinoma in situ (5.5%) and in 105/554 invasive cancers (18.9%). Survival data were available for 452 patients with invasive breast carcinoma. 14-3-3sigma cytoplasmic subcellular localization was a statistically significant prognostic factor for the whole series of invasive carcinomas, as well as for those positive for oestrogen (ER) or progesterone receptors (PR). This analysis demonstrates the utility of 14-3-3sigma as a new adjunct antibody for characterization of myoepithelial cells and myoepithelial lesions and it may be a novel prognostic factor for breast cancer patients. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.

Histochemical similarities of mucins produced by Brunner's glands and pyloric glands: A comparative study

Abstract: Mucins of the gastroduodenal junction are secreted by the mucous surface and mucus-producing glandular cells in the stomach, and by goblet cells and Brunner's glands in the duodenum Developmental studies have demonstrated that Brunner's glands can arise from undifferentiated gastric epithelium and/or intestinal epithelium in the proximal duodenum The aim of this study was to investigate the carbohydrate composition of mucins from this region and compare it with that of mucins from Brunner's glands to evaluate the probable evolution of mucins from these glands Toward that end, paraffin sections from 13 mammalian species were stained by classic carbohydrate histochemistry and treated with 13 lectins In general, the mucous surface cells of the stomach, pyloric glands, duodenal goblet cells, and Brunner's glands secretory epithelium had different lectin-binding patterns However, the lectin-binding profile of the secretory epithelium of Brunner's glands resembled that of pyloric glands more closely than that of duodenal goblet cells and mucous surface cells of the stomach Mucins from Brunner's glands and pyloric glands showed a greater terminal carbohydrate residue diversity than those of gastric mucous surface cells or duodenal goblet cells The lectin-binding profile argues for the evolution of similar mucins from the epithelia of Brunner's glands and pyloric glands The greater diversity of carbohydrate residues in mucins secreted by Brunner's glands suggests that their mucus is more adaptable This may explain why Brunner's glands metaplasia rather than goblet cell metaplasia is seen in the mucosa adjacent to chronic intestinal ulcers

Basal cell proliferations of the prostate other than usual basal cell hyperplasia: A clinicopathologic study of 23 cases, including four carcinomas, with a proposed classification

Abstract: Basaloid proliferations of the prostate with morphologic patterns other than usual basal cell hyperplasia are rare, and the distinction between benign and malignant lesions has been difficult. We describe 23 such lesions and classify them into two groups: adenoid cystic-like hyperplasia and adenoid cystic or basaloid carcinoma. Adenoid cystic-like hyperplasia (n = 19) was characterized by an older age at presentation (mean, 71.8 years), transition zone location with background of nodular hyperplasia, multifocality, lobulation, circumscription, and small acini with occasional hyalinization. A cribriform pattern limited to small- and medium-sized glands, squamous metaplasia, and hypercellular myxoid stroma were occasionally seen. Adenoid cystic carcinoma (n = 3) was characterized by a younger age at presentation (mean, 46.0 years), peripheral zone involvement, and large acini that were often dilated and exhibited extensive interanastomoses, prominent intraglandular hyalinization, perineural invasion, and extraprostatic extension. Basaloid carcinoma (n = 1) showed infiltration between normal glands, perineural invasion, and extraprostatic extension but lacked a cribriform architecture. The degree of cytologic atypia and mitotic rate overlapped between the hyperplasia and carcinoma cases. Both hyperplastic lesions and adenoid cystic carcinomas showed a basal cell phenotype with strong immunoreactivity to cytokeratins 14 and 34betaE12, but the basaloid carcinoma was negative for these markers. In all cases, the proliferating basal cells were nonreactive for myoepithelial and prostatic secretory cell markers. The 8 patients with adenoid cystic-like hyperplasia with available follow-up information had no progression of disease (mean follow-up period, 8.6 years). One patient with adenoid cystic carcinoma died with widespread metastases, but the 3 other patients with carcinomas had no disease progression (mean follow-up period, 7.0 years). In conclusion, most florid basaloid proliferations of the prostate fall into one of two categories. In the first, there is a clear association with nodular hyperplasia (adenoid cystic-like hyperplasia) and, although cytologic atypia and mitoses may be seen, they are present within a lesion that retains an orderly, vaguely nodular (noninfiltrative) pattern. The second group of cases (adenoid cystic and basaloid carcinoma) shows a widespread, haphazard infiltrative growth pattern. This study suggests that adenoid cystic carcinomas are biologically indolent following prostatectomy but have a low risk of distant metastasis.

p63 Expression in benign and malignant breast lesions

Abstract: The p63 gene encodes six protein isoforms. The transactivating isoforms have similar actions with p53, while the N-isoforms inhibit transcription activation by p53 and transactivating isoforms. p63 is expressed in stratified epithelia and in basal cells of the prostate and salivary glands. In mammary epithelium p63 has been shown to be expressed only in the myoepithelial layer. In the present study we investigated the immunohistochemical expression of p63, in benign and malignant breast lesions, and compared it with known myoepithelial cell markers. Our material consisted of 140 benign and 126 malignant breast lesions. We used the antibodies anti-p63, anti-alpha-smooth muscle actin, anti-S-100 protein and anti-cytokeratin 14. In all benign lesions, p63 immunoreactivity was noted in the myoepithelial cell layer surrounding the luminal epithelial cells. A less continuous peripheral rim of myoepithelial cells was also highlighted with p63-staining in all situ carcinomas. All invasive breast carcinomas were devoided of peripheral p63 staining. Interestingly, strong nuclear p63 immunoreactivity was noted in a small fraction (5-15%) of epithelial cells in all cases of papillomatosis, in 62.5% of in situ ductal papillary-type carcinomas and in 33.3% of invasive papillary carcinomas. Comparable staining was observed with S-100. The stromal cells were unreactive to p63. Our findings suggest that p63 is a sensitive and specific myoepithelial marker, and may be included in immunohistochemical panels aiming to identify myoepithelial cells in problematic breast lesions. Regarding papillary neoplasms, it is possible that tumor cells acquire and exhibit at least in part a myoepithelial differentiation program.

Immunostaining patterns of myoepithelial cells in breast lesions: a comparison of CD10 and smooth muscle myosin heavy chain.

Abstract: Background: Recent studies have reported CD10 expression in myoepithelial cells (MEC) of the breast, supporting its use as a marker to help distinguish invasive breast carcinoma (IC) from ductal carcinoma in situ (DCIS). Aim: To compare the effectiveness of CD10 with smooth muscle myosin heavy chain (SMMHC) in the detection of MEC in benign and malignant breast lesions. Methods: Histological material from 25 patients with DCIS and 21 with IC were immunostained for CD10 and SMMHC. Staining was scored on a scale of 0 to 3+ (0, no staining; 3+, intense) and the staining distribution was documented as focal, partial, or circumferential. Results: Uniform, 3+ circumferential CD10 and SMMHC staining of MEC was seen in normal breast ducts and lobules, and in ducts and acini involved in sclerosing adenosis and apocrine metaplasia. In an analysis of total ducts involved by DCIS, 3+ circumferential staining was seen in 65 of 366 ducts (17.7%) stained for CD10 versus 190 of 396 ducts (48%) stained for SMMHC. MEC were not detected immunohistochemically in 116 of 366 ducts (31.7%) with anti-CD10 and 50 of 396 (12.7%) with anti-SMMHC. In contrast, all ICs were negative for both CD10 and SMMHC. Focal background staining of stromal myofibroblasts was seen with both CD10 and SMMHC, but CD10 showed a higher rate of non-specific staining of epithelial cells. Conclusion: Although CD10 can aid in the distinction between IC and DCIS, SMMHC is a more sensitive and specific marker of MEC and shows less heterogeneity of immunostaining patterns.

Novel aspects in cutaneous biology of acetylcholine synthesis and acetylcholine receptors

Abstract: Extraneuronal acetylcholine (ACh) has been demonstrated to influence a plethora of cutaneous cell functions in an autocrine, paracrine and endocrine fashion. Through the differentiation-specific expression of its different nicotinic (nACh-R) and muscarinic (mACh-R) receptors, ACh acts upon keratinocyte proliferation and migration, terminal differentiation and barrier formation, sweat and sebum secretion as well as microcirculation and angiogenesis. Only very recently it has been recognized that acetylcholinesterase, but not cholineacetyltransferase, activity is regulated by hydrogen peroxide. Considering that the outer layer of the human skin can be a target for UV-generated H2O2 in the millimolar range, this mechanism needs to be taken into account for the regulation of ACh homeostasis in skin biology. Consequently, ACh can accumulate, as shown, for example, in the depigmentation process in vitiligo. There is a highly regulated distribution of ACh-R in human epidermis and adnexal structures, supporting previously observed effects of cholinergic compounds on keratinocyte biology. Most significantly, the regulated expression of ACh-R in sebaceous glands advocates a role for ACh in sebum production and as a promoter of sebocyte differentiation, thus offering an explanation for skin diseases associated with altered sebum production after chronic nicotine exposure. So far, ACh-induced sweat production has been thought to be under the exclusive control of mACh-R. However, recently, the presence of both different nACh-R and mACh-R in myoepithelial and acinar cells of eccrine sweat glands has been documented, indicating a more complex regulation of sweat production and expulsion.

Clinicopathological significance of metallothioneins in breast cancer.

Abstract: Metallothioneins (MTs) are a family of metal binding proteins that play an important role in maintaining transition metal ion homoeostasis, redox balance in the cell and fundamental cellular processes such as proliferation and apoptosis. In humans, there are 4 groups of MT proteins which are encoded by 10 functional MT isoforms. In breast tissues, MT is primarily expressed in myoepithelial and malignant epithelial cells. Immunohistochemical studies have revealed that 26% to 100% of invasive ductal breast cancers express the MT protein. The MT-1F and MT-2A isoforms have been reported to be associated with higher histological grade in breast cancer, whereas higher MT-1E mRNA expression was found in estrogen receptor-negative tumors compared to their estrogen receptor-positive counterparts. A number of studies have shown that MT expression in breast cancer is associated with poorer prognosis. In addition, metallothionein expression may have a potential role in protecting the breast cancer cell from chemotherapeutic threats to survival.

Myoepithelial cell-rich neoplasms: cytologic features of benign and malignant lesions.

Abstract: BACKGROUND Lesions that contain abundant myoepithelial cells may present as a diagnostic challenge in fine-needle aspiration (FNA) specimens. Potential diagnostic problems may arise due to morphologic heterogeneity of myoepithelial cell-rich lesions and difficulty in predicting malignancy in FNA specimens. An accurate diagnosis is important, because malignant myoepithelial cell-rich lesions require a wider local excision and lymph node dissection. The authors characterized the cytologic features of myoepithelial cell-rich lesions in an attempt to define the criteria that facilitate distinction between benign and malignant tumors. METHODS FNA biopsies of myoepithelial cell-rich lesions with corresponding histologic specimens were selected. The cytology specimens were evaluated for the following criteria: cellularity, cell morphology, pleomorphism, chromatin pattern, presence of nucleoli, background material, necrotic debris, and presence of mitotic figures. A review of the histologic sections was performed for diagnostic confirmation. RESULTS Seventeen specimens from 17 different patients were selected. The histologic diagnoses were myoepithelial carcinoma (n = 6 patients), malignant mixed tumor with predominant myoepithelial carcinoma (n = 2 patients), epithelial-myoepithelial carcinoma (n = 1 patient), and benign mixed tumor (n = 8 patients). The primary sites included the parotid gland (n = 10 patients), submandibular gland (n = 3 patients), minor salivary gland (n = 3 patients), and breast (n = 1 patient). Most specimens, whether they were benign or malignant, were very cellular. Pleomorphism, coarse chromatin, prominent nucleoli, mitotic figures, and necrosis were observed only in malignant specimens. Background material and ductal cells were seen in both benign and malignant specimens. CONCLUSIONS The presence of pleomorphism, coarse chromatin, prominent nucleoli, mitotic figures, and/or necrosis should raise the possibility of myoepithelial carcinoma in FNA specimens from myoepithelial cell-rich lesions. Cancer (Cancer Cytopathol) 2004. © 2004 American Cancer Society.

Ectopic hamartomatous thymoma: a clinicopathologic and immunohistochemical analysis of 21 cases with data supporting reclassification as a branchial anlage mixed tumor.

Abstract: This report describes the clinicopathologic and immunohistochemical findings in 21 cases of a highly distinctive tumor with a strong predilection for the lower neck region of adult males. Our study group consisted of 20 males and one female. The patients were 28 to 79 years old (mean age, 47 years; median age, 40 years), and they presented with solitary, lobular or multilobular masses ranging in size from 2.0 to 19.0 cm in greatest dimension (mean size, 5.1 cm; median, 4 cm). The tumors principally involved the lower neck region, usually in close proximity to the sternoclavicular joint. The preoperative duration of the lesions ranged from 2 months to 30 years. Histologically, the tumors were typically well marginated and composed of plump spindled cells, delicate spindled cells, mature adipose tissue, and epithelial cells, including both squamous and glandular elements. Epithelial-lined cysts were a focal finding in most cases and measured up to 2 cm in greatest dimension. Mitotic counts for the tumors ranged from 0 to 7 mitotic figures per 50 high power fields (mean mitotic count, 1.1 mitotic figures per 50 HPFs). Our immunohistochemical analysis revealed a complex immunophenotype with a diverse keratin profile. The plump spindled cells had a myoepithelial phenotype, as evidenced by the coexpression of keratins (5, 5/6, and 14), alpha-smooth muscle actin, CD10, and to a lesser extent, calponin. No compelling evidence for thymic differentiation was observed. The patients were initially managed by biopsy or partial resection (n = 4), simple local excision (n = 16), or an unspecified procedure (n = 1). Clinical follow-up of > or =3 years was available for 10 patients (48%). Two patients had recurrent disease, but there were no metastases or tumor-related deaths. A derivation from sequestered branchial epithelium is likely, but evidence for a thymic component is tenuous, at best. Our data support reclassification of this distinctive process as a branchial anlage mixed tumor. The differential diagnosis includes conventional mixed tumors of skin adnexal or salivary gland origin, synovial sarcoma, a peripheral nerve sheath tumor variant, and cystic teratoma.

Polymorphous low-grade adenocarcinoma of the major salivary glands: report of three cases in an unusual location.

Abstract: Aims : Polymorphous low-grade adenocarcinoma (PLGA) is the second most common type of malignant neoplasm in minor salivary glands. Its origin in major salivary glands is considered exceedingly rare. Herein, we present three cases of de novo PLGA arising in major salivary glands. Methods and results : Three cases of PLGA were identified in a large series of primary tumours of major salivary glands. We investigated their clinicopathological profiles, including immunohistochemical features. The three patients (two men and one woman) were 51, 65, and 79 years old. The tumours were 20–30 mm large; two were in the parotid gland and one in the submandibular gland. Histologically, all the tumours had a polymorphous architectural pattern showing predominantly solid, tubular, and cribriform features and invasive growth. Papillary areas were observed focally in two tumours and an ‘Indian-file’ array in one. The tumour cells had a bland cytological appearance and low mitotic count. Two tumours showed perineural invasion. No preexisting pleomorphic adenoma component was identified. In all cases, tumour cells were positive for epithelial markers, S100 protein, and vimentin but negative for α-smooth muscle actin, muscle-specific actin, and glial fibrillary acidic protein. Proliferative activities assessed with the Ki67 labelling index were 4.3%, 7.1%, and 7.6%; no p53 overexpression was observed. Two patients had local recurrence, but none had metastasis or died of tumour. Conclusions : PLGAs arising in major salivary glands and those in minor salivary glands have similar clinicopathological and immunohistochemical characteristics. It is important to recognize that PLGA can occur ab initio in the major salivary glands, although it is extremely rare.

Primary cutaneous mucinous carcinoma: presence of myoepithelial cells as a clue to the cutaneous origin.

Abstract: Background Primary cutaneous mucinous carcinoma (PCMC) is a rare malignancy with probable apocrine differentiation. It is important to differentiate it from metastatic mucinous carcinoma (MMC), especially from the breast. The histologic and immunohistochemical features overlap between PCMC and breast mucinous carcinomas. In this study, we introduce the presence of myoepithelial component in PCMC as a new morphologic parameter to distinguish it from MMC from either breast or sites elsewhere in the body. Materials and methods We studied 7 cases of PCMC. The possible in situ component in the tumor was assessed by the presence of a peripheral myoepithelial cell layer. Myoepithelial cell differentiation was confirmed with immunohistochemical stains for p63, CK 5/6, calponin, smooth muscle actin (SMA), HHF-35, and CD10. Estrogen and progesterone receptor (ER/PR), gross cystic disease fluid protein (GCDFP 15), CK7, CK20, and S-100 immunostains were also performed. Results Histologically, multiple small monomorphic epithelial islands floating in multilocular pools of mucin characterized the tumor. Focally, epithelial islands were bordered by dermal connective tissue at the periphery of mucin pools. Secretory snouts were apparent in all cases providing evidence for apocrine differentiation. In 5 of the 7 cases, an in situ component was identified as epithelial islands being bounded by a myoepithelial layer, which was highlighted by p63, CK 5/6, calponin, SMA, and HHF-35. ER/PR and CK7 were positive in all the cases. GCDFP-15 and CD10 were focally positive in the tumor cells and myoepithelial cells, respectively. All 7 cases were negative for S-100 and CK 20. Conclusion We conclude that an in situ component is frequently present in PCMC (5/7) and may help in distinguishing this entity from MMC, especially of breast origin. Furthermore, it may provide insight into the pathogenetic mechanism of mucinous carcinoma evolving from in situ carcinoma with luminal mucinous distention to cellular tumor with a little surrounding mucin.

[Immunohistochemical identification of lymph vessels with D2-40 in diagnostic pathology].

Abstract: D2-40 is an antibody that reliably detects human lymphatic endothelial cells. Because little is known about the extent to which other cells are stained, we have investigated this question in various tissues. Normal, reactive and neoplastic lymphatics (including lymphangiomas and Stewart-Treves syndrome) were stained by D2-40. Published findings indicate that some angiosarcomas and Kaposi are positive. Staining was also found in the following non-endothelial cells: mesothelial cells, follicular dendritic reticulum cells, Cajal cells, a few epithelial cells in the dermis, myoepithelial cells (e. g. breast), and basal cells (e. g. prostata), various mesenchymal cells. The following tumours were reactive: myofibroblastic tumours, gastrointestinal stromal tumour, mesothelioma, adenomatoid tumour, traumatic neuroma, seminoma, seminoma in situ and other testicular tumours, pleomorphic adenoma (one of two tumours positive), and follicular dendritic reticulum cell sarcoma. Despite this relatively broad spectrum of reactivity, we consider D2-40 to be the best commercially available antibody for the delineation of normal, reactive and neoplastic lymphatic endothelial cells.